Liver pathology in IBD Patients
Francesca Rosini, H-ECCO Member
Crohn’s Disease (CD) and Ulcerative Colitis (UC) are considered multisystemic diseases. They affect the gastrointestinal tract but can also involve other systems and organs. Almost 50% of patients with Inflammatory Bowel Diseases (IBDs) experience at least one extraintestinal manifestation (EIM). The principal organs and structures affected by EIMs are, amongst others, joints and bones, eyes, liver and the hepatobiliary system and skin .
The liver, in particular, is frequently involved in UC and CD. About 30% of cases of IBD are associated with altered liver function tests (LFTs) even when there is not full-blown liver disease. It has been observed that the elevation of LFTs is not associated with the IBD activity and that it can resolve spontaneously in the absence of an underlying liver condition. Nevertheless, given the high rate of hepatobiliary EIMs, it is important to monitor and investigate liver functionality in IBD patients. All IBD patients should at least be screened for viral hepatitis and for alcohol or substance abuse. In addition, in the presence of a liver injury the pattern of injury should be specifically investigated, e.g. cholestatic or hepatocellular liver injury [2, 3].
The most common EIMs involving the hepatobiliary systems are primary sclerosing cholangitis (PSC), non-alcoholic fatty liver disease and drug-induced liver injury. Other rarer conditions have been described, such as primary biliary cholangitis, granulomatous hepatitis, amyloidosis, viral hepatitis reactivation, portal vein thrombosis and liver abscesses. It is also worth mentioning that patients with IBD can develop cholelithiasis and pancreatitis .
PSC is the most common hepatobiliary manifestation in IBD. This association was described for the first time in 1874 by C.H. Thomas and then confirmed in 1899 by James Lister. The classic form of PSC affects both young and old patients, with a 2:1 male predominance. The cause is still uncertain, but several studies support an autoimmune/immune-mediated aetiology. PSC affects mainly medium and large bile ducts; it induces chronic inflammation of the biliary tree, progressive fibrosis and scarring of the liver parenchyma, which lead eventually to portal hypertension, liver failure and cirrhosis. Liver transplantation is the only available treatment option for end-stage liver disease. PSC patients also have a higher risk of developing cholangiocarcinoma.
Patients may be completely asymptomatic or show symptoms depending on the stage of the disease. Early symptoms include fatigue and itching, whereas the symptoms associated with later stages are jaundice, weight loss and severe abdominal pain in the upper right quadrant. PSC is diagnosed with a combination of serological tests and radiological exams such as endoscopic retrograde cholangiopancreatography (ERCP) and magnetic resonance cholangiopancreatography (MRCP). A liver biopsy is not always indicated but it may be needed either to confirm the clinical diagnosis when other investigations are ambiguous or to assess the stage of the disease [5–7].
About 5% of patients with UC and 3% of CD patients will develop PSC. The vast majority (about 70%–80%) of PSC patients have coexisting IBD. In such cases IBD has a specific behaviour and peculiar features and is considered a distinct phenotype known as “PSC-IBD”. Patients usually develop mild pancolitis with considerable involvement of the right colon. Furthermore, there is frequent inflammation of the terminal ileum and a relative rectal sparing. Coexisting PSC-IBD may be associated with a higher risk of dysplasia and colonic cancer, even after liver transplantation. For this reason, patients with PSC-IBD require close surveillance for colorectal cancer .
Morphologically PSC displays concentric “onion skin” fibrosis around bile ducts, portal inflammation with infiltration of the biliary epithelium, acute cholangitis and lobular cholestasis. Later stages show obliteration of the lumen of bile ducts, diffuse ductular proliferation, extensive fibrosis and cirrhosis.
Some patients have clinical, biochemical and histological features of classic PSC, but a normal cholangiogram and MRCP. This condition is known as small-duct PSC. Studies show that about 80% of patients with small-duct PSC have IBD. Amongst these, 80% have UC and the rest have CD. In the past this entity was considered an early stage of the classic form of PSC and was believed to be associated exclusively with IBD patients. Later studies, however, showed that small-duct PSC is a distinct clinical entity and can also affect non-IBD patients. Small-duct PSC has a better prognosis, with a lower risk of development of cholangiocarcinoma .
In contrast to PSC, the association between primary biliary cholangitis (PBC) and IBD is quite rare, with few reports in the literature. The presentation of PBC in IBD patients has the same clinical, serological and morphological features as PBC in non-IBD patients. UC and CD can both be associated with PBC and the prevalence is variable between studies. Despite being a rare association, PBC should be considered in IBD patients with abnormal LFTs and cholestasis. Morphologically the liver displays a dense portal lymphoplasmacytic infiltrate with inflammation of the biliary epithelium. Non-necrotising epithelioid granulomata may be present within portal areas. Bile ducts are progressively destroyed by the inflammatory process and the later stage shows bile duct loss, periportal ductular proliferation, cholestasis, severe fibrosis and cirrhosis. PBC is commonly associated with other autoimmune disorders, e.g. Sjögren syndrome and scleroderma .
IBD patients have an elevated risk of developing autoimmune diseases, including autoimmune hepatitis (AIH). The association between AIH and IBD is significantly less common than that between PSC and IBD. Only a few papers in the literature describe this pure association in both adults and paediatric patients. One study reported that 16 patients with chronic UC presented coexisting AIH without features of PSC .
IgG4-related disease is another immune-mediated multisystemic syndrome caused by an infiltration of lymphocytes and IgG4-secreting plasma cells within tissues and organs. The lymphoplasmacytic infiltrate is associated with storiform fibrosis and obliterative phlebitis. IgG4-related disease predominantly affects the hepatobiliary system, causing cholangitis and bile duct stricture which can mimic PSC. It can also affect the pancreas, leading to autoimmune pancreatitis. The association with IBD is not clear and only a few case reports are present in the literature [11, 12].
One of the most common causes of elevated LFTs in IBD patients is the presence of liver steatosis. Non-alcoholic fatty liver disease (NAFLD) is quite common in IBD patients, with a variable prevalence that ranges between 1% and 50% in UC and between 1% and 40% in CD. The histological features of NAFLD vary from liver steatosis to non-alcoholic steatohepatitis. The latter shows, along with steatosis, a neutrophilic inflammatory infiltrate, ballooning cells, Mallory-Denk bodies and pericellular or more advanced fibrosis. NAFLD can remain asymptomatic until the end-stage complications occur. The association between IBD and NAFLD comprises multiple factors, such as metabolic syndrome, older age and hepatotoxic drugs, in particular corticosteroids and methotrexate. Other factors that can contribute to development of NAFLD are duration and severity of IBD, alteration of the gut microbiota, parental nutrition and prior surgery. Screening for NAFLD should be performed in all patients presenting these risk factors [3, 5].
During the course of the disease, IBD patients may be exposed to multiple drugs, some of which have potential for liver toxicity, such as aminosalicylates, methotrexate, thiopurines, corticosteroids and biological agents. Drug-induced liver disease (DILI) may affect a vast proportion of IBD patients; for this reason, laboratory test monitoring is required. DILI can be characterised by a variety of conditions, depending on the chemical agent. Patients can show elevated transaminases, cholestasis, NAFLD (as mentioned above), granulomatous hepatitis and fibrosis . One of the major concerns associated with the use of steroids and immunosuppressor agents, such as anti-TNFα, is the risk of reactivation of hepatitis B virus (HBV). This risk varies depending on the type of immunosuppressor and the HBV phase before treatment. Clinical practice guidelines from AEEH, EASL and ECCO recommend prophylaxis against HBV reactivation in patients with IBD who are receiving immunosuppressive agents. On the other hand, immunosuppressive treatment does not appear to reactivate hepatitis C [5, 13].
Granulomatous hepatitis (GH) is an uncommon extraintestinal liver manifestation of IBD patients. Idiopathic GH is a rare condition of unknown aetiology. Drugs such as mesalazine and sulfasalazine can induce it. Granulomata in liver can be associated with a variety of conditions such as mycobacterial or parasitic infections, PBC or systemic granulomatous diseases like sarcoidosis. Patients with GH usually have recurrent fever of unknown origin, granulomata in the liver and negative serology and microbiological tests. The prevalence of GH in IBD patients is estimated to be around 1% and it is more frequent in CD. If treated, it usually has a good prognosis .
Other less common EIMs includes secondary hepatic amyloidosis, portal vein thrombosis and pyogenic liver abscess.
Secondary amyloidosis has a prevalence of about 3% in IBDs, and it is more common in CD. The chronic inflammatory process involving the gut can lead to the deposition of amyloid within tissues and organs, including the liver.
Portal vein thrombosis is a rare but very serious hepatic EIM, which has a higher incidence in IBD patients than the general population. The principal cause that leads to this condition is an inflammatory hypercoagulative state in IBD patients which may be provoked by multiple factors: inflammation, immobilisation, surgery, extent of colon disease, smoking, low platelet count and altered levels of fibrinogen and antithrombin III.
Hepatic pyogenic abscesses are also seen in IBD patients, particularly in CD patients. The mechanisms that cause the formation of liver abscesses can be the direct extension or fistulisation of intra-abdominal abscesses, malnutrition and steroid treatment. Liver abscesses are more commonly found in the right liver. Antibiotics following culture and drainage are the usual treatment [1, 4, 5].
In conclusion, EIMs involving the liver and the hepatobiliary tracts are common in IBD patients and can be heterogeneous. Careful evaluation of LFTs in IBD patients is very important in order to diagnose possible coexisting liver diseases and to provide the best management and treatment. A multidisciplinary approach is always recommended for complex cases.
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